The Webcast included a rundown on the status of the Institute's drug development pipeline, including updates on the leading therapeutic, ALS TDI 00846; recent grant and collaboration news; a recap of highlights from the 17th Annual Meeting of the International Alliance of ALS/MND Organizations, Dec. 6-7, 2009, in Berlin, and the 20th Symposium on ALS/MND Research, also held in Berlin Dec. 8-10; and an introduction to the "Dashboard," the face of the Institute's information management system.

MDA and the nonprofit biotech ALS Therapy Development Institute (ALS TDI) of Cambridge, Mass., forged an historic partnership in January 2007 when they launched the largest ALS drug discovery project to date, a three-year, $36 million collaboration to identify biochemical targets in ALS and find drugs that hit them. In January 2010 MDA renewed its partnership with ALS TDI with a grant of $2.5 million.

The compound is an antibody (immune-system protein) designed to modulate the immune response through a particular pathway called CD40L. ALS TDI scientists have determined that in mice with an ALS-like disease, CD40L pathway activity is increased ("upregulated") in the spinal cord, skeletal muscle and sciatic nerve.

Multiple ALS TDI mouse studies of the compound showed a small but significant increase in survival, muscle function and survival of motor neurons (which normally die in ALS); and a decrease in the harmful activation of normally supportive cells called astrocytes.

The compound hits the CD40L target, a particular cell-surface receptor that is present on a number of different types of cells associated with the immune system, Perrin reported.

Study data show the compound does not affect the time it takes mice to achieve their peak body weight. It does, however, slow the loss of weight after disease onset, significantly delay the progression of paralysis, and prolong survival.

Perrin noted that once scientists were confident the drug was working, they then began trying to figure out how it worked. Identifying that mechanism may help in the identification of related drugs with better safety profiles, greater specificity, or the ability to hit similar pathways that produce an even greater effect.

“It's a very important question,” said Perrin. "Once we find a drug that has an effect similar to the size of the effect we're seeing with this drug, we could treat them as a combo therapy and try to amplify the effect with a combination of the two drugs at various doses."

Study results in mice have shown that the drug knocks down almost every one of the approximately 20 genes in the CD40L pathway. But it remains to be seen whether the CD40L pathway data from mice with ALS is relevant to humans with the disease.

Over the last three years, Perrin noted, ALS TDI has partnered with several MDA clinics across the country that have been collecting samples of blood, muscle, skin and fat from people with ALS. The collection currently contains approximately 400 blood samples, which scientists at the Institute have profiled, along with an equal number of non-ALS samples, in order to measure patterns of gene activity (gene "expression"). They found a subset of patients — approximately half — have highly upregulated genes in the CD40L pathway.

Perrin affirmed that a great deal of work has been done on 00846, including testing in hundreds of mice. He said the Institute hopes to move the compound into clinical trials by the end of 2010, and that it’s working to find a pharmaceuticals partner to help move the compound through testing and into the clinic as quickly as possible.

In addition to 00846, Perrin noted, ALS TDI has many drugs in its pipeline and ALS TDI researchers are working on some 30 different potential therapeutics. For more information, see the webcast archive.

New funding, partnerships, collaborations

ALS TDI Communications Director Rob Goldstein reported on a number of developments on the Institute's funding front, including a renewal of "critical funding" from MDA.

Goldstein thanked and recognized MDA for providing "a renewal of their partnership and investment in ALS research," with the new $2.5 million grant aimed at continuing the search for therapeutic targets in ALS. The funds were awarded through MDA's Augies's Quest, the fast-track research initiative out of MDA's ALS Division. Representatives from MDA and ALS TDI, along with a number of expert ALS researchers, will review quarterly the goals and progress associated with the milestone-driven grant.

Another key funding partnership, announced Jan. 12, 2010, has come in the form of a multi-year grant awarded through the 2010 Defense Appropriations Act, signed by President Obama on Dec. 22, 2009, and provided to ALS TDI through the Department of Defense. The money will fund development and advancement of new therapeutics through ALS TDI's rigorous preclinical screening process and into the clinic.

Goldstein reported also on the Applied Proteomics partnership announced Dec. 12, 2009. The partnership is designed to identify and validate protein markers for ALS, using animal and human samples. Protein markers are changes in protein levels that correlate with disease progression. They're useful for diagnosis and analyzing response to treatment.

The work "will help us to further understand and prioritize what's going on," both in the ALS model and with human samples collected from clinics, "to identify key points that we can attack with new therapeutics," Goldstein explained. This in turn may help speed clinical trials by allowing phase 1 trials to be bypassed.

Goldstein said the proof-of-concept work is complete and data will be presented at the next ALS TDI research update Webcast in April.

Goldstein also previewed two new partnerships with biotechnology company Oxford BioMedica of Oxford, United Kingdom, and stem cell research and drug discovery company California Stem Cell, headquartered in Irvine, Calif.

Berlin recap

Perrin reported on ALS TDI's presence at the 17th Annual Meeting of the International Alliance of ALS/MND Organizations, Dec. 6-7, 2009, in Berlin, in which ALS TDI representatives gave presentations on unification in drug development as a means of bringing together wide areas of expertise and eliminating duplicated effort and wasted resources.

He commented also on the 20th Symposium on ALS/MND Research, held in Berlin immediately after the International Alliance Meeting. Highlights in research over the last year were presented at the Symposium, with particular focus on results for a number of drugs from companies such as Knopp Neurosciences and Sangamo BioSciences.

Perrin commented on the drug ceftriaxone, an antibiotic that has been tested in the SOD1 mouse model and shown to increase the production of a specific set of transporters that work to remove a chemical called glutamate, which is secreted by support cells called astrocytes and which can be toxic to nerve cells.

Perrin said that although ALS TDI was unable to replicate the mouse findings, the clinical data presented in Berlin from the first two stages of human trials is "quite compelling," and "warrants further study."

According to principal investigator Merit Cudkowicz, the trial is an "adaptive design study with three stages," the first two of which were used to determine the optimum dosage to be used in the third stage. Enrollment for the third stage, designed to test for efficacy, began in June 2009, and currently continues at 46 centers in the U.S. and Canada. Twelve additional centers are nearly ready to begin enrollment as well. For more information on the ceftriaxone trial, visit the clinical trials section on MDA's Web site.

Perrin also briefed viewers on "The Dashboard," the face of the ALS TDI information management system that is an effort to bring together all information on ALS, including thoughts and comments on journal papers and related literature, processes in the lab, and any relevant "information in the scientist's brain."

The Dashboard electronically captures data and puts it into a database, and tracks scientist input. It's hoped it will inspire ideas that lead to projects and then serve as a project management tool by helping researchers gauge where the project stands, what's holding it up and how to proceed.